The 2-aryl propionic acids are an important subclass of non-steroidal anti-inflammatory compounds having high analgesic properties. These compounds have been shown to be effective against pain and inflammatory action. In addition, some of the 2-aryl-propionic acids have been shown to possess non-steroidal anti-inflammatory activity and possess mechanism of action beyond the classical cyclooxygenase pathway inhibition.
Many of the 2-aryl propionic acids, such as, ibuprofen and kekoprofen, exists as racemates. See F. Jamali, European. Journal. Drug. Metab. Pharmacokinet., 1988, 13, 1-9; Hurt, et al., in J. Pharm. Pharmacol., 1983, 35, 693-704; and Jamali, et al. in J. Pharm. Sci., 1989, 78, 695-715.
It has been shown that with respect to the 2-aryl propionic acids that exist as enantiomers, the more active form is the S-enantiomer, while the R-enantiomer is either inactive or has reduced activity. Furthermore, with respect to the efficacy of the R-enantiomer of the 2-aryl propionic acid, it has been suggested that its activity is due in part to an in vivo inversion of the R-stereoisomers to the active Senantiomer. However, in vivo and in vitro investigations clearly show that the S-enantiomeric form is the more pharmacologically active stereoisomer.
Thus, the S-enantiomer is the more desired stereoisomer. The S-enantiomer has several therapeutic advantages. For example, less S-enantiomer is required than the corresponding racemic or the R-enantiomer to achieve a desired biological effect. Consequently, in order to achieve an efficacious response, less S-stereoisomer relative to the corresponding R-enantiomer or racemic mixture needs to be administered. Furthermore, the skilled artisan would expect less side effects using the S-enantiomers than with the racemic mixture or with the R-isomer. Finally, drug action of the S-enantiomer is faster then with the racemic mixture since the receptors are enantiospecific having a high intrinsic infinity for the S-enantiomeric molecules.
Therefore, it is desirable to have a preparation of S-enantiomers of the 2 aryl-propionic acid with high optical purity that can be produced in an efficient manner. At present, only a few methods for a stereospecific chemical synthesis for 2 aryl propionic acids are known for industrial application. While many approaches have been developed, the majority of them lack simplicity and high stereoselectivity. See for example, Luball, et al., JACS, 1988, 110, 7447; Kagan, et al. in "New Approaches in Asymmetric Synthesis" in Topics in Stereochemistry. For example, .alpha.-hydroxy esters as the chiral agents (Lassen, in JACS, 1989, 111, 670-7691) or asymmetric ketones, Paradies, et al. in Pharmaceutical Manufacturing, 1991, 192-196, as the chiral agents have been utilized in stereospecific synthesis.
Optically active alpha-alkyl-aldehydes have been prepared through the intermediacy of an imine or a hydrazone. See, for example, Bergbreiter, et al., 1983, "Alkylation of Imine and Amine Salts", in Asymmetric Synthesis, editor J. D. Morrison, Orlando, Fla., Academic Press, Vol. 2A, page 243; D. Enders, "Alkylation of Chiral Hydrazones" in Asymmetric Synthesis, Ed. J. D. Morrison, Orlando, Fla., Academic Press, Volume 30, page 275; and Meyers, et al. in J. Org. Chem. 1978, 43, 892.
However, the present process provides an inexpensive and facile synthetic route for the preparation of S-aryl propionic acids in high enantiomeric excess. The key to the synthetic route of optically pure enantiomers of 2-aryl alkanoic acids, especially S or R- arylpropionic acids, is the formation of the corresponding 2-aryl-alkyl aldehyde which can be easily oxidized to the 2-aryl propionic acid. The aldehyde formed in accordance with the present invention is optically active and formed in enantiomeric excess and is prepared using relatively inexpensive and readily available starting materials as described herein. By using the present process, the enantiomers of 2-aryl alkyl aldehydes and 2-aryl alkanoic acids are formed in high chemical yields and both can be formed in the S-configuration with greater than 95% optical purity.